The overall goal of this proposal is to use an isolated, isovolumic retrograde blood perfused rabbit heart to evaluate the stability of the lumped constant in the 18F-2-fluoro-deoxyglucose (FDG) tracer kinetic model and the ability of the model to accurately measure exogenous glucose metabolism under conditions of altered substrate supply, coronary blood flow and mechanical workload. The FDG tracer kinetic model requires three different parameter measurements to estimate glucose consumption: 1) the lumped constant, 2) the rate constants describing exchange between the three compartments of the model, and 3) tissue 18FDG content. In the present proposal, we will measure these three parameters in an in vitro preparation to evaluate their accuracy and reproducibility. Once these parameters are known, the lumped constant, together with independently determined plasma glucose and FDG concentrations and the model predicted tissue FDG-6-PO4 will be used with the FDG operational equation to compute exogenous glucose consumption from a single measurement of tissue 18F content. Two other methods of computing myocardial glucose consumption from multiple measurements of tissue 18F content will also be evaluated. The results of all three approaches will be compared to Fick determined glucose metabolic rate. In the first project, the possibility will be investigated that 2-3H- glucose can be used to assess the rate constants of glucose membrane transport and phosphorylation using the FDG model. It is hypothesized that 2-3H-glucose undergoes only membrane transport and phosphorylation in its labeled form because of the documented rapid exchange of 3H-label in the 2 position with unlabeled cytoplasmic water during the hexose isomerase reaction. In the second and fourth projects, the stability of the lumped constant will be evaluated under conditions in which available evidence suggests its possible instability. In the second project, the lumped constant will be evaluated in the presence and absence of insulin in order to change the rate limiting step in FDG extraction from the phosphorylation reaction to membrane transport. In the fourth project, the stability of the lumped constant will be evaluated under altered cardiac loading and blood flow conditions. The third and fifth projects will evaluate the ability of the model to accurately measure myocardial glucose consumption under conditions that are identical to that used for evaluation of the lumped constant. Completion of these projects should provide new information which might help in the use of FDG and positron emission tomography to quantify glucose utilization in patients.
| Marshall, R C; Powers-Risius, P; Huesman, R H et al. (1998) Estimating glucose metabolism using glucose analogs and two tracer kinetic models in isolated rabbit heart. Am J Physiol 275:H668-79 |
| Marshall, R C; Taylor, S E; Powers-Risius, P et al. (1997) Kinetic analysis of rubidium and thallium as deposited myocardial blood flow tracers in isolated rabbit heart. Am J Physiol 272:H1480-90 |
